The nucleus accumbens (Acb) is crucially involved in mediating the reinforcing actions of drugs of abuse such as cocaine, and 'natural'reinforcers such as food and water. The PI completed a series of electrophysiological studies that examined the activity of the same Acb neurons in rats responding on multiple schedules for either two 'natural'reinforcers (water and food), or one of those 'natural'reinforcers and the intravenous self-administration of cocaine (Carelli et al., 2000). The results showed that the majority of neurons tested exhibited similar, overlapping neuronal firing patterns across the two 'natural'reinforcer conditions. In contrast, the majority of neurons examined (>90%) exhibited differential, nonoverlapping firing patterns relative to operant responding for water (or food) versus cocaine reinforcement. Those findings provide important insight into the functional microcircuitry in the Acb that underlies reward processing and goal-directed behavior (Carelli and Wightman, 2004). Here, four specific aims are proposed to expand those findings and examine complex interactions between cellular discharges and behavior related to cocaine versus 'natural'rewards. Since natural rewards are typically devalued in cocaine addicts in comparison with drugs of abuse, Exp. 1 will determine if alterations in Acb cell firing occur during presentation of a natural reward that predicts access to cocaine. In the last funding period, the PI reported dynamic increases in the percentage of Acb neurons that encode cocaine-directed behaviors following interruption of cocaine access (abstinence). Exp. 2 will determine if those findings are generalizable to natural rewards by determining the effects of interruption of access to sucrose on Acb cell firing characteristics during sucrose-directed behavior. Exp. 3 will expand our abstinence studies and determine if separate neural circuits in the Acb encoding cocaine versus natural reward remain evident following interruption of cocaine access. Exp. 4 will determine if medial prefrontal cortical (mPFC) neurons are responsive to cocaine-associated stimuli before versus following cocaine abstinence, a phenomenon well-documented for Acb cells in a number of reports by the PI. The results are directly relevant to understanding the biological basis of stimulus control in human cocaine addiction in which stimuli previously associated with drug taking are strong elicitors of 'craving'and often lead to relapse following periods of drug abstinence (O'Brien et al., 1992;Childress et al., 1999).